The actions of the adipocyte-derived hormone leptin on lipid metabolism are proposed to be important in preventing the development of tissue lipotoxicity and lipid-related insulin resistance. This is best illustrated in leptin-deficient states, where the administration of exogenous leptin corrects systemic dyslipidemia, excessive storage of lipid in peripheral tissues such as the liver, and insulin resistance associated with this condition. Furthermore, states of leptin resistance such as human obesity and diet-induced obesity (DIO) are characterized by a similar metabolic phenotype to leptin deficient conditions, implicating a role for a loss of leptin action in the pathogenesis of the metabolic abnormalities of obesity. However, despite some progress, our understanding of the mechanisms of leptin regulation of lipid metabolism and insulin action, and the mechanisms of leptin resistance remains poor. Our recent work has focused on the effects and mechanisms of leptin action on lipid metabolism .in liver, a central organ in the regulation of whole-body lipid homeostasis. In brief these studies established a novel role for leptin in the acute regulation of hepatic lipid levels, an effect that is impaired in obesity, and identified a biochemical mechanism for this defect. Specifically, we have demonstrated (i) that leptin rapidly (within approximately 100 min) decreases liver triglyceride levels;(ii) that DIO induces resistance to the acute triglyceride-lowering effects of leptin;(iii) that activation of liver PI3-kinase is required for the effects of leptin on hepatic triglyceride levels, and (iv) that defective leptin activation of liver PI3-kinase is a novel mechanism of leptin resistance in obesity. The central objective of the current proposal is to extend these studies to determine (i) the lipid metabolic pathways in liver acutely regulated by leptin;(ii) the biochemical/molecular mechanisms of leptin action on hepatic lipid metabolism;(iii) the interactions of insulin and leptin on hepatic metabolism, and (iv) the biochemical mechanisms of hepatic leptin resistance in obesity. In undertaking these studies, we will increase our understanding of the mechanisms of leptin action and the contribution of leptin resistance to the metabolic abnormalities of obesity.